17alpha-carboxyethyl-6-halo-17beta-hydroxyan-drost-4-en-3-one lactones and intermediates



Un t 5 m Patent f i7... 4'CARBOXYETHYL-6-HALO-l7fl-HYDROXYAN-, ,gi z g sg t-nN-s-om LA'CTONES AND INTERME- Roy Hfllible, In, Morton Grove, 111., assignor to G. D.

I I seam &fCo., Chicago, 111., a corporation of Delaware 5 No Drawing. Filed Aug. 7,1959, Ser. No. 832,176

' Claims. c1. 260-23257) This invention relates to 17a-carboxyethyl-6-halo17,8- hydroxyandrost-4-en-3-one lactones, processes for their manufacture, and intermediates whereby these processes proceed. More particularly, this invention relates to compounds of the formula wherein X signifies a halogen atom as above and Z represents hydrogen, an alkali metal, or the ammonium radical. Those skilled in the art will appreciate that the described salts readily derive from the corresponding lactones on contact with aqueous alkali. The free acids, in turn, are obtained from the salts by a critically brief exposure to a proton source; prolongation of the exposure time induces lactonization.

The compounds of this. invention are useful because of their valuable pharmacological properties. For example, they are potent diuretics, being adapted to block the efiec't of desoxycorticosterone acetate'on urinary sodium and potassium. It follows that the intermediates from whichlthese compounds can be obtained are also useful. 1

Manufacture of the subject compounds starts with 17w (Z-carbdxyethyl)androst-5-ene-3B,17y3-diol 'y-lactone, an embodiment of the invention disclosed and claimed in United States Patent No. 2,705,712 to John A; Cella.

2,946,787 Patented July 26, 1960 ice I -v 2 chloride in. pyridine affords the desired 60: and 6,9 epimers, respectively. I

Alternatively, 17a-(2 carboxyethyl) 17/3 hydroxyandrost-4-en-3-one lactone, another embodiment of the invention of John-A. 'Cella disclosed in US. 2,705,712, is heated 'in carbon tetrachloride with the appropriate N- halosuccinimide to'give the corresponding 6fl-haloicompound of this invention, which isomerizes to the Got-epimet on' contact with hydrogen halide in acetic acid.

The following examples describe in detail compounds illustrative of the presentfinvention and methods which have been devised for their manufacture. *However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees centigrade and relative amounts of materials in parts by weight, except as otherwise noted.

This material is converted tothe 50:;6oz-6POXid6 with perbenzoic acid in benzene solution, and the corresponding halohydrin is formed therefrom by incorporation of the elements of the appropriate hydrohalide. The 3-alcohol function is then oxidized to a ketone with chromium trioxide in acid acetone medium, whereupon dehydration with hydrogen chloride in acetic acid or with thionyl Example 1 A. 17a (2 carboxyethyl) -5a,6a-ep0xyandrosmne-3p, 17 3-diol -lactone.A solution of approximately 44 parts of perbenzoic acid in 600 parts of benzene is added to a suspension of 99 parts of 17a-(2-carboxyethyl)-androst- -ene-3/3,17fl-diol 'ylact0ne and 5 parts of anhydrous sodium acetate in 1400 parts of benzene. The resultant mixture islet' stand at room temperatures for 1 /2 hours, whereupon it is washed with aqueous 5% sodium bicarbonate and then with water until the washings are neutral. The mixture is next dried over anhydrous sodium sulfate and finally stripped of solvent by distillation. The residue comprises a mixture of a and B epoxides which is separated by fractional crystallization from a'mixture of acetone and petroleum ether. The a-epoxide, being less soluble than its epimer, is preferentially precipitated, leaving the j3-epoxide in the mother liquors. The 17oc-(2- carboxyethyl)-5a,-6a-epoxyandrostane-3 3,17fl-diol 'y-lactone thus obtained melts in the range 2335-2415 (with sublimation) and has a specific rotation of,96.

B. 170; (2 cwrboxyethyl)-6fi-fluoroandrostane-3B,5a, 17,8-tri0l 'y-lact0ne.To a solution of 87 parts of 17a- (2- carboxyethyl)-5u,6a-epoxyandrostane-3fl,l7fi-diol 'y-lactone in a mixture of 5500 parts of anhydrous benzene with 4300 parts of anhydrous ether is added 97 parts of boron fluoride ethyl ether. The resultant mixture is let stand at room temperatures for 4 /2 hours, whereupon a small amount of insoluble material is filtered out and the filtrate is stripped of solvent by distillation. The residue is 17x-(2-carboxyethyl)-6fi-fluoroandrostane 35,504,175- triol 'y-lactone.

C. 17u-'(2-cwrboxyethyl) -6/3-flu0r0-5a,17fl dihydroxyandrostan-3-0ne -Iact0ne.-To a solution of 87 parts of 17a- Z-carboxyethyl -6fi-fiuoroandrostane-3B,5a, l7fl-trio1 'y-lactone in 1040 parts of acetone is slowly added, with vigorous agitation at room temperatures, a solution of 12 parts of chromium trioxide and 18 parts of concentrated sulfuric acid in 45 parts of water. Sufi'icient 2- pr'opanol is then introduced to destroy excess chromium trioxide, whereupon 5000 parts of water is added. The solid precipitate which forms is collected on a'filter and washed thereon with Water. Recrystallized from methanol, it melts at 225-229 (with decomposition). This material is 17a-(2-carboxyethyl)-6fi-fiuoro-5a,17/3dihydroxyandrostan-3-one 'y-lactone.

'D. 170; (2 carboxyethyl) 6a flzmro 17p hydr0xymndr0st-4-en-3-onelqctoma-Anhydrous hydrogen chloride is bubbled through a solution of 71 parts of 170:-

androstan-3-one 'y-lactone in 5700 parts of glacial acetic acid at approximately 20 :for 1 /2 hours. The resultant' solution is let stand at room temperatures for /2 hour, then poured into 40,000 parts of water. The mixture so produced is extracted with ether. The ether extract is washed successively with aqueous sodium bicarbonate and water, whereupon it is dried over anhydrous calcium.

Example 2 17a (2 carboxyethyl) 6p fluoro 17B hydroxy androst-4-en3-0ne lactone.-To a solution of 8 parts of 17a (2 carboxyethyl) 6/8 fluoro 50;,1719 dihydroxyandrostan-B-one 'y-lactone in 80 parts of pyridine at approximately 5 is added parts of thionyl chloride. The resultant mixture is stirred for 5 minutes, then diluted with 2000 parts of water. The mixture so produced is extracted with ether. The ether extract is washed with water, dried over anhydrous'sodium sulfate, and stripped of solvent by distillation. The residue is 17a.(2-carboxyethyl)-6/3-fluoro-17B-hydroxyandrost-4-en-3-one lactone, which is characterized by a maximum in the ultraviolet absorption spectrum at 234 millimicrons, with a molecular extinction coefficient of 12,500. The product has the formula A, 17oz (2 carboxyethyl) 65 chloroandrostane- 3115a,] 7B-triol v-lactona-To a solution of 9 parts of 17a (2 carboxyethyl) 50;,60; epoxyandrostane 318, 176-diol 'y-lactone in 670 parts of dichloromethane is added approximately 45 0 parts of concentrated hydrochloric acid. The resultant mixture is stirred for 20 minutes, then diluted with water. The aqueous phase is separated and discarded. The organic phase is successively washed with .water, and aqueous sodium bicarbonate and finally water again, whereupon it is dried over anhydrous sodium sulfate and stripped of solvent by distilla tion. The residue, recrystallized from acetone, affords pure 17a (2 carboxyethyl)-6p-ch1oroandrostane-3fl,5a, 17fi-trio1 'y-lactone, which melts at approximately 189- 190 (with decomposition).

B. (2 carboxyethyl) 6B chloro-5a,17 3-dihydroxyandrostan-3-one y-lactone.--Using the technique of Example 10, but substituting 87 parts of 17m-(2-carboxyethyl)-6 8-chloroandrostane-3/3,5a,17/8-triol 'y-lactone for the l7a-(2 carboxyethyl)'-6;9-fluoroandrostane-3fl,5a,17;8- triol y-lactone called for therein, one obtains: l7u-(2-ca r boxyethyl) -6;8-'chloro-5 a, I7fi-dihydroxyandrostan-3 -one 7- lactone.

C. 1704 (2 carboxyethyl) 60p chl0ro-- 17B hydroxyandrost4-en-3-one lactone.-Using the technique of Example 1D, but substituting 71 parts of l7a-(2-carboxyethyl)-6,9-chloro-5a,l7 8-dihydroxyandrostan 3-one y-lactone for the 71 parts of l7a-(2-carboxyethyl) -6p-fluoro- 5a,17,3-dihydroxyandrostan-3-one 'y-lactone called for therein, one obtains l7a-(2-carboxyethyl)-6a-chloro-17phydroxyandrost-4-en-3-one laetone, of the formula A Example 4 Example 5 6,3 bromo 17a (2 carboxyethyl') 17,8v hydr oxyandrost-4-en-3-one lactone.-- To 34 parts of 17ct-(2-carboxyethyl)-17fi-hydroxyandrost-4en-3-one lactone dissolved in 1600 parts of warm carbon tetrachloride is added, with agitation, 18 parts of N-bromosuccinimide. An exothermic effect produces gentle boiling which is sustained for one hour by heating with continued agitation under reflux. The reaction mixture is then cooled to room temperature and filtered. vThe filtrate isfreed of solvent by vacuum distillation, leaving an oily residue which solidifies on trituuation with hexane. Recrystallization from a mixture of. acetone and hexane affords pure 6;? bromo 17oz .(2 earboxyethyl) 17B hydroxy androst-4-en-3-one lactone, which melts in the range 'on carbon atom 6 with halogen.

143.5-148" (with decomposition). The product has the 4. 17a (2 carboxyethyl)-6fi-fluoro-17p-hydroxyanformula drost-4-en-3-one lactone.

5. As an intermediate, 17a-(2-carhoxyethyl)-6fl-fiuoroo 5a,17p-dihydroxyandrostan-3-one y-lactone.

5 6. A compound of the formula mo mo What is claimed is: 0=- 1. A compound of the formula 01 0 wherein Cl denotes replacement of one of the hydrogens on carbon atom 6 with chlorine.

7. 17a. (2 carboxyethyl)-6a-ch1oro-17fi-hydroxyandrost-4-en-3-one lactone.

8. As an intermediate, 17u-(2-carboxyethyl)-6B-ch1oroandrostane-3p,5a,17B-trio1 'y-lactone.

9. A compound of the formula o o T x H(]\ wherein X denotes replacement of one of the hydrogens 80 2. A compound of the formula H10 wherein Br denotes replacement of one of the hydrogens m0 on carbon atom 6 with bromine,

40 10. 6p-bromo-17cc-(2 carboxyethyl)-17fi-hydroxyandrost-4-en-3-one lactone.

F v References Cited in the file of this patent wherein F denotes replacement of one of the hydrogens Fried et al.: J.A.C.S., vol. 76, pages 1455-6 (1954). on carbon atom 6 with fluorine. Bowers et a1.: J.A.C.S., vol. 80, pages 4423-4 (1958). 3. 17a (2 carboxyethyl)-6a-fluoro-17fl-hydroxyan- Hogg et a1.: Chem. and Ind., pages 1002-3, August 9,

drost-4-en-3-one lactone. 

1. A COMPOUND OF THE FORMULA 